The goal of the proposed experiments remains the characterization of cellular mechanisms underlying glutamate neurotoxicity, a process which likely participates in the neuronal degeneration associated with certain acute or chronic neurological diseases. Furthermore, independent of direct disease implications, elucidation of these mechanisms may yield insights into the general nature of neuronal injury, and thus aid in the development of neuroprotective strategies. To resolve specific cellular and molecular events, experiments will be carried out in vitro, either in primary cortical cell cultures, or in mammalian cell lines transfected with cloned glutamate receptors. Answers to three questions will be sought: l. How does metabotropic glutamate receptor activation influence excitotoxicity? 2. Does the calcium influx triggered by activation of different defined glutamate receptors predict subsequent excitotoxic death even in non-neuronal, HEK 293 cells? 3. Which pathways mediate the late toxic influx of Ca2+ into neurons that follows brief intense NMDA receptor activation? In particular, does the NMDA-induced late inward current described by Chen and Wong on hippocampal neurons, play a role? Improved definition of the cellular mechanisms underlying glutamate neurotoxicity could lead to the development of new therapeutic maneuvers designed to attenuate the neuronal destruction associated with several disease states. Furthermore, such a definition would likely provide sorted insight into the general problem of neuronal cell injury. and might thus have valuable implications for understanding human neurological illness.